Hu Y, Coates A R M, Mitchison D A
Medical Microbiology, Department of Cellular & Molecular Medicine, St George's Hospital, University of London, London, United Kingdom.
Int J Tuberc Lung Dis. 2008 Jan;12(1):69-73.
To measure the bactericidal activity of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis, strain H37Rv, in the three Hu/Coates models of bacterial persistence, in comparison with the activity of moxifloxacin (MXF), a drug shown to be likely to shorten treatment in current clinical trials.
The bactericidal activity of a wide range of PA-824 and MXF concentrations was tested against a 100-day static, starved, anaerobically-adapted culture in Model 1. In Models 2 and 3, rifampicin (RMP) 100 mg/ml was added to the 100-day culture for 5-7 days and bactericidal activities against surviving tolerant bacilli were tested by addition of the test drugs after removal of RMP in Model 2, and during exposure to RMP in Model 3.
PA-824 exhibited little bactericidal activity at low concentrations up to 1.25 microg/ml in each of these models, but high concentrations of >or=10 microg/ml showed considerable bactericidal activity, sufficient to kill all bacilli in Model 3, and appreciably greater than with MXF. However, as PA-824 is 94% plasma bound, concentrations of free drug sufficient to reach the zone of high bactericidal activity may not be obtained in cavities of pulmonary tuberculosis.
与在当前临床试验中显示可能缩短治疗时间的莫西沙星（MXF）的活性相比，在三种细菌持续存在的Hu/Coates模型中，测定硝基咪唑并吡喃PA - 824对结核分枝杆菌H37Rv菌株的杀菌活性。
在模型1中，针对100天的静态、饥饿、厌氧适应培养物，测试了广泛浓度范围的PA - 824和MXF的杀菌活性。在模型2和3中，向100天培养物中加入100 mg/ml利福平（RMP）5 - 7天，在模型2中去除RMP后加入测试药物，在模型3中RMP暴露期间，测试对存活的耐受杆菌的杀菌活性。
在这些模型中，PA - 824在高达1.25μg/ml的低浓度下几乎没有杀菌活性，但浓度≥10μg/ml时显示出相当大的杀菌活性，足以在模型3中杀死所有杆菌，且明显大于MXF。然而，由于PA - 824与血浆的结合率为94%，在肺结核空洞中可能无法获得足以达到高杀菌活性区域的游离药物浓度。
